Modification of a natural diterpene and its antitumor mechanism: Promoting apoptosis, suppressing migration, and inhibiting angiogenesis

[Display omitted] •A TPP-linked 3,4-seco-sonderianol derivative was designed and prepared.•The derivative can induce A549 cell apoptosis via the mitochondrial pathway.•The derivative suppressed tumor by regulating STAT3 and FAK signaling pathways.•The derivative inhibited angiogenesis.•The derivative possessed in vivo tumor activity. The synthesis or derivation of a series of structural analogues based on natural products is a common strategy for discovering antitumor drugs. As a unique natural diterpene derived from Trigonostemon howii, 3,4-seco-sonderianol (1) exhibited moderate cytotoxic effects. To improve the activity, a new diterpene derivative (1b) with a mitochondrial targeting function was synthesized by coupling triphenylphosphine to compound 1. Compared to the parent molecule, the antitumor activity of 1b increased greatly. A series of mechanistic experiments revealed that compound 1b induced cancer cell apoptosis and inhibited cancer cell migration by targeting the mitochondria and regulating the STAT3 and FAK signaling pathways. Meanwhile, 1b was found to inhibit angiogenesis in a transgenic zebrafish model. It is worth noting that 1b also demonstrated excellent antitumor effects in zebrafish tumor xenotransplantation models. All the evidence supports that compound 1b targeting mitochondria has the potential to be a candidate for an antitumor drug.